Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey

Tomohiro Nishimura, Nobuyuki Amano, Yoshiyuki Kubo, Midori Ono, Yukio Kato, Hisashi Fujita, Yoshiaki Kimura, Akira Tsuji

研究成果: Article

33 引用 (Scopus)

抄録

Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1%, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.

元の言語English
ページ(範囲)1275-1284
ページ数10
ジャーナルDrug Metabolism and Disposition
35
発行部数8
DOI
出版物ステータスPublished - 2007 8
外部発表Yes

Fingerprint

Macaca fascicularis
Midazolam
Metabolism
Biological Availability
Haplorhini
Small Intestine
Rats
Metabolites
Pharmaceutical Preparations
Oral Administration
Theoretical Models
Tissue
Mathematical models
Liver

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

これを引用

Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey. / Nishimura, Tomohiro; Amano, Nobuyuki; Kubo, Yoshiyuki; Ono, Midori; Kato, Yukio; Fujita, Hisashi; Kimura, Yoshiaki; Tsuji, Akira.

:: Drug Metabolism and Disposition, 巻 35, 番号 8, 08.2007, p. 1275-1284.

研究成果: Article

Nishimura, Tomohiro ; Amano, Nobuyuki ; Kubo, Yoshiyuki ; Ono, Midori ; Kato, Yukio ; Fujita, Hisashi ; Kimura, Yoshiaki ; Tsuji, Akira. / Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey. :: Drug Metabolism and Disposition. 2007 ; 巻 35, 番号 8. pp. 1275-1284.
@article{a055eae9573146c59998a611a852f7c0,
title = "Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey",
abstract = "Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1{\%}, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.",
author = "Tomohiro Nishimura and Nobuyuki Amano and Yoshiyuki Kubo and Midori Ono and Yukio Kato and Hisashi Fujita and Yoshiaki Kimura and Akira Tsuji",
year = "2007",
month = "8",
doi = "10.1124/dmd.106.013037",
language = "English",
volume = "35",
pages = "1275--1284",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "8",

}

TY - JOUR

T1 - Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey

AU - Nishimura, Tomohiro

AU - Amano, Nobuyuki

AU - Kubo, Yoshiyuki

AU - Ono, Midori

AU - Kato, Yukio

AU - Fujita, Hisashi

AU - Kimura, Yoshiaki

AU - Tsuji, Akira

PY - 2007/8

Y1 - 2007/8

N2 - Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1%, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.

AB - Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1%, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.

UR - http://www.scopus.com/inward/record.url?scp=34547209778&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547209778&partnerID=8YFLogxK

U2 - 10.1124/dmd.106.013037

DO - 10.1124/dmd.106.013037

M3 - Article

C2 - 17470527

AN - SCOPUS:34547209778

VL - 35

SP - 1275

EP - 1284

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 8

ER -